MED25

Summary

MED25 (mediator complex subunit 25, HGNC:28845) is a protein-coding gene on chromosome 19q13.33, encoding Mediator of RNA polymerase II transcription subunit 25 (Q71SY5). Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. It is a selective cancer dependency (DepMap: 19.5% of cell lines).

This gene encodes a component of the transcriptional coactivator complex termed the Mediator complex. This complex is required for transcription of most RNA polymerase II-dependent genes. The encoded protein plays a role in chromatin modification and in preinitiation complex assembly. Mutations in this gene are associated with Charcot-Marie-Tooth disease type 2B2.

Source: NCBI Gene 81857 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital cataract-microcephaly-nevus flammeus simplex-severe intellectual disability syndrome (Definitive, GenCC) — +2 more curated relationships
• Clinical variants (ClinVar): 838 total — 2 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 1
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 19.5% of screened cell lines
• MANE Select transcript: NM_030973

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28845
Approved symbol	MED25
Name	mediator complex subunit 25
Location	19q13.33
Locus type	gene with protein product
Status	Approved
Aliases	ARC92, ACID1, TCBAP0758, DKFZp434K0512
Ensembl gene	ENSG00000104973
Ensembl biotype	protein_coding
OMIM	610197
Entrez	81857

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 14 protein_coding, 4 retained_intron

ENST00000312865, ENST00000538643, ENST00000593595, ENST00000593636, ENST00000593767, ENST00000594998, ENST00000595185, ENST00000599722, ENST00000861899, ENST00000861900, ENST00000861901, ENST00000861902, ENST00000861903, ENST00000861904, ENST00000861905, ENST00000929728, ENST00000929729, ENST00000929730

RefSeq mRNA: 2 — MANE Select: NM_030973 NM_001378355, NM_030973

CCDS: CCDS33075, CCDS92667

Canonical transcript exons

ENST00000312865 — 18 exons

Exon	Start	End
ENSE00000720687	49830511	49830598
ENSE00000864571	49831936	49832021
ENSE00000864576	49834986	49835177
ENSE00001126687	49830088	49830218
ENSE00001126742	49830694	49830887
ENSE00001126829	49836847	49836979
ENSE00001706125	49828449	49828547
ENSE00001731650	49819172	49819296
ENSE00001792578	49829786	49829948
ENSE00001792658	49828970	49829090
ENSE00002431227	49832100	49832157
ENSE00003508890	49836226	49836406
ENSE00003550855	49835727	49835945
ENSE00003563651	49835534	49835605
ENSE00003586033	49818571	49818616
ENSE00003598505	49818289	49818475
ENSE00003648299	49831333	49831461
ENSE00003648669	49832308	49832415

Expression profiles

Bgee: expression breadth ubiquitous, 269 present calls, max score 98.45.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 44.9446 / max 544.6819, expressed in 1823 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
177071	44.8823	1823
177072	0.0622	11

Top tissues by expression

292 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	98.45	gold quality
secondary oocyte	CL:0000655	97.78	gold quality
right testis	UBERON:0004534	96.92	gold quality
left testis	UBERON:0004533	96.89	gold quality
right adrenal gland cortex	UBERON:0035827	96.77	gold quality
right adrenal gland	UBERON:0001233	96.60	gold quality
right uterine tube	UBERON:0001302	96.50	gold quality
left adrenal gland cortex	UBERON:0035825	96.33	gold quality
left adrenal gland	UBERON:0001234	96.19	gold quality
adrenal cortex	UBERON:0001235	96.01	gold quality
blood	UBERON:0000178	94.99	gold quality
hindlimb stylopod muscle	UBERON:0004252	94.98	gold quality
bronchial epithelial cell	CL:0002328	94.95	gold quality
adrenal gland	UBERON:0002369	94.71	gold quality
gastrocnemius	UBERON:0001388	94.44	gold quality
testis	UBERON:0000473	94.32	gold quality
lower esophagus mucosa	UBERON:0035834	94.10	gold quality
adenohypophysis	UBERON:0002196	93.77	gold quality
apex of heart	UBERON:0002098	93.64	gold quality
right ovary	UBERON:0002118	93.53	gold quality
body of stomach	UBERON:0001161	93.43	gold quality
left ovary	UBERON:0002119	93.17	gold quality
muscle of leg	UBERON:0001383	93.16	gold quality
pituitary gland	UBERON:0000007	93.10	gold quality
right lobe of thyroid gland	UBERON:0001119	92.97	gold quality
left lobe of thyroid gland	UBERON:0001120	92.82	gold quality
epithelium of bronchus	UBERON:0002031	92.80	gold quality
bronchus	UBERON:0002185	92.44	gold quality
granulocyte	CL:0000094	92.40	gold quality
thyroid gland	UBERON:0002046	92.24	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.83
E-MTAB-6075	no	172.89
E-CURD-112	no	2.73

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

3 targets.

Target	Regulation
RARA	Activation
RXRA	Activation
THRA	Repression

Upstream regulators (CollecTRI, top): ESR1, RARA, THRA

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 19.5% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 27)

• cloned a prostate-derived cDNA encoding a novel protein with a predicted molecular weight of 78 kDa (P(78)), and precisely mapped the cDNA sequence to chromosome 19 (PMID:12163014)
• biochemical purification and cloning of ARC92; identified as a specific cellular interaction partner of the VP16 activation domain (PMID:14983011)
• data suggest that MED25, in cooperation with CBP and Mediators through its distinct domains, imposes a selective advantage on RAR/RXR activation (PMID:17641689)
• Data show that Med25 is coordinately expressed with Pmp22 gene dosage and expression in transgenic mice and rats, and suggest a potential role of this protein in the molecular etiology of Charcot-Marie-Tooth disease. (PMID:19290556)
• Lana-1-induced serum response element activation was inhibited by the dominant-negative N-terminal domain of the human MED25 mediator subunit, suggesting that this subunit mediates Lana-1-induced serum response element activation. (PMID:20089804)
• Preliminary NMR chemical shift mapping showed that VP16 H2 (VP16C) interacts with MED25 ACID through one face of the beta-barrel, defined by strands B4-B7-B6. (PMID:20974256)
• MED25 and PTOV1 differentially modulate retinoic acid sensitivity in cancer cells depending on their expression levels. (PMID:21110951)
• These results define a role for Med25 and the Mediator complex in the regulation of xenobiotic metabolism and lipid homeostasis. (PMID:21135126)
• A hydrophobic furrow, formed by a beta-barrel and two alpha-helices in MED25 VBD, interacts tightly with VP16 TADn (PMID:21378963)
• report the NMR structure of the Mediator subunit Med25 (also called Arc92) activator interaction domain (ACID) and analyze the structural and functional interaction of ACID with the archetypical acidic transcription activator VP16 (PMID:21378965)
• The regulatory interaction between Sox9, Wwp2 and Med25 defines the Sox9 transcriptional mechanisms of chondrogenesis in the forming palate. (PMID:21427722)
• solution NMR structure of protein MED25(391-543), comprising the activator interacting domain of subunit 25 of mediator, is presented with the measurement of polypeptide backbone heteronuclear 15N-{1H} NOEs to identify fast internal motional modes (PMID:21785987)
• the identification of MED25 as one of the HNF4alpha binding partners in pancreatic ss-cells leading to insulin secretion which is impaired in MODY patients (PMID:22952853)
• Mediator subunit MED25 plays a critical role in this process and identify a MED25 domain that serves as a docking site on Mediator for the ATF6alpha transcription activation domain. (PMID:23864652)
• Med25 is identified as a new coactivator of ERalpha that is required for ERalpha-mediated regulation of CYP2C9 expression (PMID:24960263)
• MED25 is important for regulating the epigenetic landscape resulting in transcriptional activation of a highly inducible gene, CYP2C9 (PMID:25391650)
• the critical region of chromosome 19 a homozygous variant (c.418C>T, p.Arg140Trp) in Mediator complex subunit 25 predicted as deleterious. (PMID:25527630)
• Homozygous MED25 mutation implicated in eye-intellectual disability syndrome. (PMID:25792360)
• A model is proposed in which the N-terminal transactivation domain of ERM binds the MED25 VP16 H1 binding pocket in a helical conformation. (PMID:26130716)
• Med25, a variable member of the Mediator complex, is a coactivator of ligand-activated ERalpha that interacts with ERalpha through its C-terminal LXXLL motif after BPA exposure, and is functionally involved in BPA-induced transcriptional regulation of CYP2C9 expression and enzyme activity. (PMID:27273787)
• recurrent MED25 frameshift mutation in the C7 repeat (c.602delC) that would result in a frameshift mutation (p. Pro201ArgfsX13) were detected in the colorectal cancers with microsatellite instability-high, but not in those with microsatellite-stability (PMID:27406034)
• FOS strongly binds to the same MED25 site as ETV4 activation domain and JUN interacts with the other two MED25 sites. (PMID:28728983)
• Further delineation of Basel-Vanagaite-Smirin-Yosef syndrome: Report of three patients. (PMID:32324310)
• Analysis of P(78): A Novel Cytoplasmic Membrane-Associated Protein Encoded on Chromosome 19q13.3 in Glioma Specimens. (PMID:32367506)
• Improving the phenotype description of Basel-Vanagaite-Smirin-Yosef syndrome, MED25-related: polymicrogyria as a distinctive neuroradiological finding. (PMID:32816121)
• Multivalent and Bidirectional Binding of Transcriptional Transactivation Domains to the MED25 Coactivator. (PMID:32825095)
• An Unexpected Encounter: Respiratory Syncytial Virus Nonstructural Protein 1 Interacts with Mediator Subunit MED25. (PMID:36102648)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	med25	ENSDARG00000038005
mus_musculus	Med25	ENSMUSG00000002968
rattus_norvegicus	Med25	ENSRNOG00000020363
drosophila_melanogaster	MED25	FBGN0038760
drosophila_melanogaster	CG13609	FBGN0039170

Paralogs (1): PTOV1 (ENSG00000104960)

Protein

Protein identifiers

Mediator of RNA polymerase II transcription subunit 25 — Q71SY5 (reviewed: Q71SY5)

Alternative names: Activator interaction domain-containing protein 1, Activator-recruited cofactor 92 kDa component, Mediator complex subunit 25, p78

All UniProt accessions (3): Q71SY5, M0QYR4, M0QZQ2

UniProt curated annotations — full annotation on UniProt →

Function. Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors. Required for RARA/RXRA-mediated transcription.

Subunit / interactions. Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP. Interacts with CREBBP. Interacts with ESR1, GR, RARA, RXRA and THRB in a ligand-dependent fashion. Binds the Herpes simplex virus activator VP16.

Subcellular location. Nucleus.

Tissue specificity. Ubiquitously expressed. Highest levels in brain, heart, kidney, peripheral leukocytes, placenta, skeletal muscle and spleen.

Disease relevance. Charcot-Marie-Tooth disease, axonal, type 2B2 (CMT2B2) [MIM:605589] A recessive axonal form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 group are characterized by signs of axonal degeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy. The disease is caused by variants affecting the gene represented in this entry. Basel-Vanagaite-Smirin-Yosef syndrome (BVSYS) [MIM:616449] An autosomal recessive syndrome characterized by eye, brain, cardiac and palatal abnormalities as well as growth retardation, microcephaly and severe intellectual disability. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the Mediator complex subunit 25 family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q71SY5-1	1	yes
Q71SY5-4	4
Q71SY5-5	5
Q71SY5-6	6

RefSeq proteins (2): NP_001365284, NP_112235* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR021394	Med25_PTOV	Domain
IPR021397	Mediator_Med25_SD1	Domain
IPR021419	Mediator_Med25_VWA	Domain
IPR036465	vWFA_dom_sf	Homologous_superfamily
IPR038196	Med25_PTOV_sf	Homologous_superfamily

Pfam: PF11232, PF11235, PF11265

UniProt features (67 total): strand 20, helix 12, region of interest 8, compositionally biased region 8, sequence conflict 6, splice variant 3, sequence variant 3, mutagenesis site 2, turn 2, chain 1, modified residue 1, short sequence motif 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
9CCV	X-RAY DIFFRACTION	2.53
7EMF	ELECTRON MICROSCOPY	3.5
8GXS	ELECTRON MICROSCOPY	4.16
8T9D	ELECTRON MICROSCOPY	4.66
7LBM	ELECTRON MICROSCOPY	4.8
8GXQ	ELECTRON MICROSCOPY	5.04
2KY6	SOLUTION NMR
2L23	SOLUTION NMR
2L6U	SOLUTION NMR
2XNF	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q71SY5-F1	64.18	0.27

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (1): 725

Mutagenesis-validated functional residues (2):

Position	Phenotype
646	abrogates interaction with rara.
649–650	abrogates interaction with rara.

Function

Pathways and Gene Ontology

Reactome pathways

15 pathways

ID	Pathway
R-HSA-1989781	PPARA activates gene expression
R-HSA-212436	Generic Transcription Pathway
R-HSA-381340	Transcriptional regulation of white adipocyte differentiation
R-HSA-9833110	RSV-host interactions
R-HSA-1266738	Developmental Biology
R-HSA-1430728	Metabolism
R-HSA-1643685	Disease
R-HSA-400206	Regulation of lipid metabolism by PPARalpha
R-HSA-556833	Metabolism of lipids
R-HSA-5663205	Infectious disease
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-9820952	Respiratory Syncytial Virus Infection Pathway
R-HSA-9824446	Viral Infection Pathways
R-HSA-9843745	Adipogenesis

MSigDB gene sets: 378 (showing top): REACTOME_TRANSCRIPTIONAL_REGULATION_OF_WHITE_ADIPOCYTE_DIFFERENTIATION, MODULE_255, GOBP_POSITIVE_REGULATION_OF_DNA_TEMPLATED_TRANSCRIPTION_INITIATION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, MODULE_317, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_NEGATIVE_REGULATION_OF_FIBROBLAST_PROLIFERATION, EFC_Q6, BILD_HRAS_ONCOGENIC_SIGNATURE, GOBP_POSITIVE_REGULATION_OF_BINDING, GOBP_POSITIVE_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_POSITIVE_REGULATION_OF_MOLECULAR_FUNCTION, GOBP_REGULATION_OF_DNA_TEMPLATED_TRANSCRIPTION_INITIATION, MODULE_301, SCHAEFFER_PROSTATE_DEVELOPMENT_6HR_DN

GO Biological Process (8): negative regulation of transcription by RNA polymerase II (GO:0000122), positive regulation of transcription elongation by RNA polymerase II (GO:0032968), positive regulation of chromatin binding (GO:0035563), positive regulation of transcription by RNA polymerase II (GO:0045944), negative regulation of fibroblast proliferation (GO:0048147), RNA polymerase II preinitiation complex assembly (GO:0051123), positive regulation of transcription initiation by RNA polymerase II (GO:0060261), positive regulation of mediator complex assembly (GO:2001178)

GO Molecular Function (4): transcription coactivator binding (GO:0001223), nuclear retinoic acid receptor binding (GO:0042974), nuclear retinoid X receptor binding (GO:0046965), protein binding (GO:0005515)

GO Cellular Component (5): nucleus (GO:0005634), nucleoplasm (GO:0005654), transcription regulator complex (GO:0005667), mediator complex (GO:0016592), core mediator complex (GO:0070847)

Reactome top-level categories

Rollup of top-11 pathways:

Category	Pathways
Regulation of lipid metabolism by PPARalpha	1
RNA Polymerase II Transcription	1
Adipogenesis	1
Respiratory Syncytial Virus Infection Pathway	1
Metabolism of lipids	1
Metabolism	1
Disease	1
Gene expression (Transcription)	1
Viral Infection Pathways	1
Infectious disease	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
positive regulation of transcription by RNA polymerase II	2
transcription initiation at RNA polymerase II promoter	2
negative regulation of DNA-templated transcription	1
transcription elongation by RNA polymerase II	1
positive regulation of DNA-templated transcription, elongation	1
regulation of transcription elongation by RNA polymerase II	1
chromatin binding	1
positive regulation of binding	1
positive regulation of DNA-templated transcription	1
negative regulation of cell population proliferation	1
fibroblast proliferation	1
regulation of fibroblast proliferation	1
transcription preinitiation complex assembly	1
regulation of transcription initiation by RNA polymerase II	1
positive regulation of DNA-templated transcription initiation	1
positive regulation of protein-containing complex assembly	1
mediator complex assembly	1
regulation of mediator complex assembly	1
transcription coregulator binding	1
nuclear receptor binding	1
nuclear retinoic acid receptor binding	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular anatomical structure	1
protein-containing complex	1
core mediator complex	1
nuclear protein-containing complex	1
RNA polymerase II transcription regulator complex	1

Protein interactions and networks

STRING

1510 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MED25	MED6	O75586	803
MED25	MED15	Q96RN5	736
MED25	MED17	Q9NVC6	690
MED25	SYN3	O14994	665
MED25	MED23	Q9ULK4	648
MED25	SYN2	Q92777	628
MED25	CAMK2G	Q13555	589
MED25	SYN1	P17600	581
MED25	GTF2B	Q00403	543
MED25	WWP2	O00308	541
MED25	MED14	O60244	533
MED25	VWF	P04275	494
MED25	MED26	O95402	455
MED25	MED7	O43513	430
MED25	MED19	A0JLT2	416

IntAct

192 interactions, top by confidence:

A	B	Type	Score
MED10	MED19	psi-mi:“MI:0914”(association)	0.910
MED10	MED19	psi-mi:“MI:0915”(physical association)	0.910
CDK8	MED14	psi-mi:“MI:0914”(association)	0.900
MED4	MED19	psi-mi:“MI:0914”(association)	0.900
MED29	MED19	psi-mi:“MI:0914”(association)	0.890
MED21	MED19	psi-mi:“MI:0914”(association)	0.880
CDK8	MED19	psi-mi:“MI:2364”(proximity)	0.850
CDK8	MED19	psi-mi:“MI:0914”(association)	0.850
MED11	MED19	psi-mi:“MI:0914”(association)	0.840
MED18	MED19	psi-mi:“MI:0914”(association)	0.840
MED17	MED19	psi-mi:“MI:0914”(association)	0.840
MED20	MED19	psi-mi:“MI:0914”(association)	0.840
MED1	MED19	psi-mi:“MI:0914”(association)	0.840
MED19	MED7	psi-mi:“MI:0914”(association)	0.840
MED10	MED14	psi-mi:“MI:0914”(association)	0.830

BioGRID (181): MED25 (Affinity Capture-MS), MED25 (Affinity Capture-MS), MED25 (Co-fractionation), MED25 (Co-fractionation), UL48 (Reconstituted Complex), DREB2A (Co-crystal Structure), DREB2A (Reconstituted Complex), MED25 (Proximity Label-MS), MED25 (Affinity Capture-MS), MED25 (Affinity Capture-MS), MED25 (Affinity Capture-MS), MED25 (Affinity Capture-MS), MED25 (Affinity Capture-MS), MED25 (Affinity Capture-MS), MED25 (Affinity Capture-MS)

ESM2 similar proteins: A0A3Q7JC00, A0JM64, A0JNC2, A2VE44, A4IHD9, B2C6R6, B5DE09, B8BCZ8, E7F1H9, F4JT98, O09000, O57539, P78364, Q0WVM7, Q15596, Q17BA4, Q2NLB0, Q3TCX3, Q5RDA3, Q5TP13, Q5ZL54, Q61026, Q64028, Q6GP15, Q6K271, Q6NS15, Q6PEH8, Q71SY5, Q7XYY2, Q7ZVN7, Q80TM6, Q8C7E9, Q8CHY6, Q8HXM1, Q8IZL2, Q8VCB2, Q8W234, Q90WJ3, Q924H2, Q940A7

Diamond homologs: A0A3Q7JC00, A2VE44, A4IFC9, A4IHD9, Q5U2W6, Q6GP15, Q6PEH8, Q71SY5, Q86YD1, Q8VCB2, Q91VU8, Q9VCB1, Q9VDR1

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
MED25	“form complex”	“Core mediator complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 85 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Respiratory Syncytial Virus Infection Pathway	26	78.8×	1e-42
Adipogenesis	27	65.0×	8e-42
RSV-host interactions	26	62.6×	6e-40
Regulation of lipid metabolism by PPARalpha	27	58.6×	2e-40
Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	17	56.4×	1e-24
Transcriptional regulation of white adipocyte differentiation	27	53.9×	1e-39
Epigenetic regulation of gene expression by MLL3 and MLL4 complexes	17	51.5×	6e-24
Epigenetic regulation by WDR5-containing histone modifying complexes	17	40.4×	5e-22

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of transcription elongation by RNA polymerase II	23	87.6×	2e-37
RNA polymerase II preinitiation complex assembly	23	79.1×	1e-36
positive regulation of transcription initiation by RNA polymerase II	23	79.1×	1e-36
transcription initiation at RNA polymerase II promoter	7	33.2×	2e-07
somatic stem cell population maintenance	10	31.4×	1e-10
transcription by RNA polymerase II	7	6.2×	6e-03
protein ubiquitination	10	5.2×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

838 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	4
Uncertain significance	346
Likely benign	400
Benign	26

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
203445	NM_030973.4(MED25):c.116A>G (p.Tyr39Cys)	Pathogenic
2285740	NM_030973.4(MED25):c.781_791del (p.Pro261fs)	Pathogenic
1064794	NM_030973.4(MED25):c.820-1G>A	Likely pathogenic
3063666	NM_030973.4(MED25):c.2T>G (p.Met1Arg)	Likely pathogenic
421748	NM_030973.4(MED25):c.1165del (p.Leu389fs)	Likely pathogenic
504289	NM_030973.4(MED25):c.1939C>T (p.Arg647Ter)	Likely pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

4758 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:49818406:T:A	I22N	1.000
19:49818408:G:A	E23K	1.000
19:49818409:A:T	E23V	1.000
19:49818424:T:C	L28P	1.000
19:49818472:T:A	I44N	1.000
19:49818605:T:C	F57L	1.000
19:49818607:C:A	F57L	1.000
19:49818607:C:G	F57L	1.000
19:49819187:T:C	Y66H	1.000
19:49819187:T:G	Y66D	1.000
19:49819190:A:C	S67R	1.000
19:49819192:C:A	S67R	1.000
19:49819192:C:G	S67R	1.000
19:49819194:T:A	L68H	1.000
19:49819194:T:C	L68P	1.000
19:49819202:T:C	F71L	1.000
19:49819203:T:C	F71S	1.000
19:49819204:C:A	F71L	1.000
19:49819204:C:G	F71L	1.000
19:49819272:T:C	F94S	1.000
19:49819284:T:C	L98P	1.000
19:49828451:T:C	F103S	1.000
19:49828460:G:A	G106E	1.000
19:49828477:A:C	S112R	1.000
19:49828479:C:A	S112R	1.000
19:49828479:C:G	S112R	1.000
19:49828492:G:A	G117R	1.000
19:49828492:G:C	G117R	1.000
19:49828493:G:A	G117E	1.000
19:49828496:T:A	L118H	1.000

dbSNP variants (sampled 300 via entrez): RS1000103339 (19:49820574 A>G), RS1000175515 (19:49838027 G>A), RS1000305017 (19:49840551 C>T), RS1000605020 (19:49832631 G>A), RS1000744399 (19:49827898 A>G), RS1000962320 (19:49817871 C>T), RS1000974519 (19:49823293 A>G), RS1000975406 (19:49835470 T>C), RS1001055001 (19:49825340 C>T), RS1001116313 (19:49825978 T>A,C), RS1001168847 (19:49826201 C>A,T), RS1001322913 (19:49830515 C>T), RS1001571875 (19:49822122 G>A), RS1001659384 (19:49831630 G>A), RS1001723384 (19:49820211 C>G,T)

Disease associations

OMIM: gene MIM:610197 | disease phenotypes: MIM:616449, MIM:605589, MIM:118220, MIM:209850

GenCC curated gene-disease

Disease	Classification	Inheritance
congenital cataract-microcephaly-nevus flammeus simplex-severe intellectual disability syndrome	Definitive	Autosomal recessive
Charcot-Marie-Tooth disease type 2B2	Supportive	Autosomal recessive
autosomal recessive non-syndromic intellectual disability	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Charcot-Marie-Tooth disease type 2B2	Disputed	AR

Mondo (8): Charcot-Marie-Tooth disease type 2 (MONDO:0018993), congenital cataract-microcephaly-nevus flammeus simplex-severe intellectual disability syndrome (MONDO:0014643), neurodevelopmental disorder (MONDO:0700092), Charcot-Marie-Tooth disease type 2B2 (MONDO:0011570), Charcot-Marie-Tooth disease (MONDO:0015626), polyneuropathy (MONDO:0001824), autism (MONDO:0005260), autosomal recessive non-syndromic intellectual disability (MONDO:0019502)

Orphanet (4): Autosomal dominant Charcot-Marie-Tooth disease type 2 (Orphanet:64746), Basel-Vanagaite-Smirin-Yosef syndrome (Orphanet:464738), Charcot-Marie-Tooth disease type 2B2 (Orphanet:101101), Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy (Orphanet:166)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0000717	Autism

GWAS associations

0 associations (top):

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D001321	Autistic Disorder	F03.625.164.113.500
D002607	Charcot-Marie-Tooth Disease	C10.500.300.200; C10.574.500.495.200; C10.668.829.800.300.200; C16.131.666.300.200; C16.320.400.375.200
D065886	Neurodevelopmental Disorders	F03.625
D011115	Polyneuropathies	C10.668.829.800
C537991	Charcot-Marie-Tooth disease, Type 2B2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5169169 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

1 potent at pChembl≥5 of 1 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.64	IC50	2300	nM	NORSTICTIC ACID

PubChem BioAssay actives

1 with measured affinity, of 3 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
5,13,17-trihydroxy-7,12-dimethyl-9,15-dioxo-2,10,16-trioxatetracyclo[9.7.0.03,8.014,18]octadeca-1(11),3(8),4,6,12,14(18)-hexaene-4-carbaldehyde	1870203: Inhibition of Med25 transcriptional activation in human MCF-7 cells by fluorescence polarization assay	ic50	2.3000	uM

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	affects expression, increases abundance, increases expression	2
Smoke	decreases expression, increases abundance, increases expression	2
Cadmium Chloride	decreases expression, increases expression	2
TAK-243	increases sumoylation	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects binding, increases reaction, affects cotreatment, increases activity, increases expression	1
beta-lapachone	decreases expression	1
methylparaben	increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
NSC 689534	affects binding, decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Leflunomide	decreases expression	1
Acetaminophen	decreases expression	1
Benzo(a)pyrene	decreases methylation	1
Copper	affects binding, decreases expression	1
Doxorubicin	decreases expression	1
Estradiol	increases expression, affects binding, increases reaction, affects cotreatment, increases activity	1
Gallic Acid	decreases expression	1
Ozone	affects expression, increases abundance	1
Plant Extracts	affects cotreatment, decreases expression	1
Thimerosal	decreases expression	1
Thiram	increases expression	1
Gold Compounds	increases expression	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5125514	Binding	Inhibition of Med25 transcriptional activation in human MCF-7 cells by fluorescence polarization assay	Inhibitor Screen Identifies Covalent Inhibitors of the Protein Histidine Phosphatase PHPT1. — ACS Med Chem Lett

Clinical trials (associated diseases)

203 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT05902351	Not specified	RECRUITING	Natural History Study for Charcot Marie Tooth Disease
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge